Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in newborns, particularly in preterm infants. In industrialized countries, earlier diagnosis and advances in neonatal critical care have improved survival. In developing countries, improved survival of low birth weight infants is being accompanied by an increase in NEC cases without parallel improvement in management due to resource constraints. Research on affordable interventions to improve NEC outcomes is needed. Vitamin A (VA), typically low in preterm infants, is an essential nutrient for maintaining gut integrity, immune competence and other host defenses. Experimental VA deficiency produces lesions in the gut and changes in immunity similar to those caused by NEC. It is plausible that reductions in early infant death following newborn VA receipt of high-potency VA, as reported from South Asia, may have been mediated, in part, by enhanced protection against NEC. Thus, a relevant question is whether VA can improve NEC outcomes in undernourished populations. To address this question, we propose to conduct a randomized, double-blinded, placebo-controlled VA supplementation trial in Bangladesh, at the Shishu Children's Hospital in Dhaka, a national pediatric referral center. The aims are to evaluate the efficacy of VA supplementation in: 1) reducing inflammatory cytokine expression;2) ameliorating severity and duration of symptoms;and 3) decreasing risks of disease progression and mortality in newborns with NEC. Quantifying these pathways and effects of VA may help to improve treatment efficacy and provide new insights to preventing NEC in developing countries. The study builds on clinical trial research currently underway between Johns Hopkins University (JHU) and Shishu Hospital. The study is proposed as part of a K01 award to prepare the PI as an independent investigator in nutritional immunology. The PI candidate will be guided by Drs. West, Bream, and Bourgeois at JHU, who will work with him through combined directed readings, coursework, laboratory training in nutrition, microbiology and immunology, training in clinical trial conduct, and supervising his international, collaborative research. In the short term, the candidate will gain skills to characterize interactions of VA, infection and cytokine expression through laboratory and field investigation, while the study contributes evidence on the potential roles of VA in treating and preventing severe pediatric diseases associated with malnutrition.